Many hormones and neurotransmitters regulate physiological functions through specific receptor proteins located on the cell membrane. Many of these receptor-proteins transduce signals into the cell by activating a guanosine triphosphate binding protein (occasionally, referred to as “G protein” below) that is coupled to them. These receptor proteins are thereby named as G protein-coupled receptors. Since they have a common structure, composed of seven transmembrane regions, they are also generally called “seven-transmembrane receptor proteins.”
G protein-coupled receptors, which are expressed on the surface of cells in vivo and functioning cells of tissues, play an extremely important role as a target of molecules such as hormones, neurotransmitters, and biologically active compounds, which regulate the functions of these cells and tissues. Therefore, G protein-coupled receptor proteins have received great attention as targets in drug-development.
G protein-coupled receptors reported so far include: muscarinic acetylcholine receptors M1, M2, M3, and M4 (Peralta et al., EMBO J., 6:3923–3929 (1987)), muscarinic acetylcholine receptor M5 (Bonner et al., Neuron, 1:403–410 (1988)), adenosine receptor A1 (Libert et al., Science, 244:569–572 (1989)), α1A adrenoreceptor (Bruno et al., Biochem. Biophys. Res. Commun., 179:1485–1490 (1991)), β1 adrenoreceptor (Frielle et al., Proc. Natl. Acad. Sci. USA, 84:7920–7924 (1987)), angiotensin receptor AT1 (Takayanagi et al., Biochem. Biophys. Res. Commun., 183:910–916 (1992)), endothelin receptor ETA (Adachi et al., Biochem. Biophys. Res. Commun., 180:1265–1272 (1991)), gonadotropin releasing factor receptor (Kaker et al., Biochem. Biophys. Res. Commun., 189:289–295 (1992)), histamine receptor H2 (Ruat et al., Proc. Natl. Acad. Sci. USA, 87:1658–1672 (1992)), neuropeptide Y receptor Y1 (Larhammar et al., J. Biol. Chem., 267:10935–10938 (1992)), interleukin-8 receptor IL8RA (Holmes et al., Science, 2563:1278–1280 (1991)), dopamine receptor D1 (Mahan et al., Proc. Natl. Acad. Sci. USA, 87:2196–2200 (1990)), metabolic glutamate receptor mGluR1 (Masu et al., Nature, 349:760–765 (1991)), and somatostatin receptor SS1 (Yamada et al., Proc. Natl. Acad. Sci. USA, 89:251–255) (for reference, Watson S. and Arkinstall S., The G protein Linked Receptor FactsBook, Academic Press (1994)). Examples of developed medicines aimed at G protein-coupled receptors are: terazosine hydrochloride (antihypertensive agent, α1 adrenoreceptor antagonist), atenolol (antiarrhythmia, β1 adrenoreceptor antagonist), dicyclomine hydrochloride (antispasmodic agent, acetylcholine receptor antagonist), ranitidine hydrochloride (drug for peptic ulcers, histamine receptor H2 antagonist), trazodone hydrochloride (antidepressant, serotonin receptor 5-HT1B antagonist), and buprenorphine hydrochloride (analgesic agent, opioid receptor κ agonist) (for reference, Stadel et al., Trends Pharm. Sci., 18:430–437 (1997); Medicine Handbook 5th edition, Yakugyo-Jiho).
The hypothalamus, a part of the brain which governs a number of programs that trigger a particular response, contributes to the homeostasis of the internal environment by means of a variety of outputs, as the center of the autonomic nervous system. For instance, it releases hormones such as thyrotropic hormone-releasing hormone, gonadotropic hormone-releasing hormone, and growth hormone-releasing hormone, and thereby regulates the entire endocrine system through the actions of these hormones on the specific receptors expressed in target cells. These outputs in the hypothalamus are thought to be mediated by receptors expressed in the hypothalamus and compounds reacting with them. Therefore, elucidation of the relationship between the compounds regulating the hypothalamus outputs and their specific receptors expressed in the hypothalamus is extremely important in developing novel medicines for the treatment of diseases arising from endocrine disorders.